kondori_final physiology of fetal circulation_bw

8/10/2019 Kondori_Final Physiology of Fetal Circulation_bw

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Physiology of Fetal Circulation

G. Ganesh Konduri, MD

Medical College of WI

Milwaukee, WI

Disclosure

Plagiarism = Copy material from one

source

Research = Copy material from multiple

sources


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Outline

Arrangement of fetal circulation

Different segments of fetal circulation

-Placenta pulmonary circulation

Developmental changes

Transition at birth

Function of Circulatory System

Provide oxygen and nutrient supply to the

tissues

Adjust the oxygen supply to the metabolic

needs of the tissues

Return deoxygenated blood and CO2 tothe organ of gas exchange


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Normal Fetus

Satyan

Fetal Circulation


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Normal

FetalCirculation

PlacentaUA

UVIVC

Liver

SVC

Aorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO

Placental Circulation


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DV

PDA

PFO

Arrows indicate sites of

arterio-venous shunts inthe placenta

Vessel PO2

Maternal Uterine art 90-100

Inter-villous space 50

Umbilical artery 20

Umbilical vein 30-35

Chorionic villus

Branch Villus

Intervillous space

(Maternal blood)

(50)

(20)(35)

() PO2

(100)

Hb-O2 Dissociation Curve

Fetal Hb=70% Term Neo

P50= 20-HbF, 28-HbA

90%= 45-HbF. 60-HbA


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right shift left shift

temperature high low

DPG high low

p(CO2) high low

p(CO) low high

pH (Bohr effect) low (acidosis)high

(alkalosis)

type of

hemoglobin

adult

hemoglobin

fetal

hemoglobin

Hb-O2 Dissociation Curve

Normal

Fetal

CirculationPlacenta

UA

UVIVC

Liver

SVCAorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO

85

35

70

50

65

65

55


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Oxygen Content of Blood at

Different Levels of Oxygen Tension

PO2 (torr) SO2 (%) O2 Combined

with Hb

(ml/100ml)

O2 dissolved

in plasma

(ml/100ml)

Total O2content per

100ml of

blood

25 (Hb=16) 65 13.95 0.075 14.01

90 (Hb=16)

90 (Hb=12)

100

100

21.4

16.08

0.3

0.3

21.74

16.38

600 (Hb=16) 100 20.1 1.8 21.9

Modified from Cyanosis in the newborn infants Joseph Kitterman, MD Pediatrics in

Review Vol 4 (1) July 1982

Hb binds 1.34 ml O2/gm

Dissolved O2 = 0.3 ml/100 mmHg

Normal

Fetal

CirculationPlacenta

UA

UVIVC

Liver

SVCAorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO


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Left LobeRight Lobe

3-9 mmHg

10-20 cm/s

60-80 cm/s

30-50% of UV

Blood across DV


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Normal

FetalCirculation

PlacentaUA

UVIVC

Liver

SVC

Aorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO

Percent Combined Output20 Wks 30 Wks 38 Wks

Combined

output

210 ml/min 960 ml/min 1900

ml/min

Left Ventr 47 43 40

Right Ventr 53 57 60

PFO 40 30 28

Lungs 5 10 12


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Developmental Limitations

30% of fetal (premature) myocardial cell

consists of myofibrils (60% of adult

myocyte)

Myofibrils less Ca++ sensitive

Mitochondrial size & complexity less in

fetus

More dependent on carbohydrate forenergy

Fetal/neonatal myocardial physiology

Fetus/ Neonate Adult

Cardiac output HR dependent SV & HR

Starling response limited normal

Compliance less normal

Afterload compensation limited effective

Ventricular high relatively low

interdependence


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Changes at birth

SVR increases suddenly

Pulmonary flow increases by 10-fold

Left ventricle-increases in pre-load

& after-load

Increased oxygen supply- improved left

ventricular performance


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Normal

FetalCirculation

PlacentaUA

UVIVC

Liver

SVC

Aorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO

Response to Physiologic Stimuli

Stimulus PDA Pulm Artery

Hypoxia Dilate Constrict

Acidosis Dilate Constrict

Alkalosis Constrict Dilate

Oxygen Constrict Dilate


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PGE2 Effects on PDA

Endothelial Cell

Smooth Muscle Cell

PGE2

cAMPPDE3

AMP

Relaxation

Low PO2 High luminal pressure

COX

Placental PGE2

EP2 EP3 EP4

K+ K+ATP


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Normal

Fetal

CirculationPlacenta

UA

UVIVC

Liver

SVCAorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

FO


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20 weeks 28 weeks 36 weeks

40-Fold increase in # small blood vessels in 3 trimester

Increase in smooth muscle layer around small PA Increase in responsiveness of PA to stimuli

Fetal Pulmonary Circulation

Systemic Blood PressurePulmonary arterial pressure


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Low PO2

NO, PGI2ET-1, EET, TxA2

cGMP, cAMPCa++

K+Ca, Kv

Pre-pro-ET-1 Big-ET1

ET-1

ECE

ET-A

Ca++

Contr

ET-B

eNOS

NOCa++Relax

Endothelin Effects on Vessel

(203 AA)(92 AA)

(21 AA)


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VascularResistance

BloodFlow

Arteria

lPressure

(mmHg/m

l/min/kg)

(ml/min/kg)

(m

mHg)

50

40

30

20

10

0450

400

350

300

250

200

150

100

501.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0 95 136 Birth 1-3 6 days Age

80% decrease in 24 h


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Transition of Lung at Birth

20 >100

4020

Fetus Newborn

Transition in Pulm Flow

0

100

200

300

400

500

600

700

800

BL Drain lq Dist Dist+O2

Leftpulm

flow(ml/min)

*

*

*


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Oxygen

Hyperbar O2

3 Atm

Oxygen & Pulmonary Flow

0

100

200

300

400

500

600

700

800

BL Norm O2 Hyperbar O2

Fetal PO2 22 27 47

Leftpulm

flow(ml/min)


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2

Oxygen & Pulmonary Flow

0

100

200

300

400

500

600

700

800

BL Norm O2 Hyperbar O2

Control

N-LA

Fetal PO2 22 27 47


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2

ATP AMPAden

NO PG

Oxygen

ADP

Pulmonary

artery Fetal RBC

Alveolus

0

1

2

3

4

5

6

7

8

9

Bl 10% 21% 100%

ATP

0

200

400

600

800

1000

1200

1400

0

0.2

5

0.5 1 2 4 8

ATP ADP AMP

Plasma ATP level (M) Left Pulmonary Flow (ml/min)

*

*

*

**

* *

**

*

**

*

*

ATP conc. MFiO2


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2

ATP, VEGF

Ligand

Receptor

Oxygen, Distension

eNOSL-arginine L-citrulline

NO

COX PGISAA

PGI2

Adenylate

Cyclase

PDE3PDE5

sGC

GTP

cGMPGMP

ATP

AMP

cAMP

Pulmonary

Artery

Pulmonary flow and Maturation ofPulmonary flow and Maturation of

NOS & COXNOS & COX

0.4 0.8 birth0

20

40

60

80

100

120

Pulmflowas%c

ardiacoutput

0.4 0.8 Birth0

20

40

60

80

100

120

NOS

COX-1


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2

BH4BH4

Serine 1177Serine 1177 --PP

ThrThr--497497 PP

NADPHNADPH HemeFe3+

OO22

OO22--..

CaveolinCaveolin--11

ee--ee-- ee--

LL--ArgArg

NHNH22IIII

CCII

NONO O =CO =CII

LL--CitrCitr

Hsp90Hsp90

ee--ee--

FMNFAD CaM

Akt

Reactive Oxygen Species

O2_ NO

eNOS

H2O2

H2O + O2

Peroxynitrite

Constriction

SOD

cGMP

Vasodilation

NOX, NOS


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2

eNOS COX SOD

NO PGI2

cGMP cAMP

Endo

Smooth

muscle

Estrogen, Steroids, Shear stress

O2_

Regulation of cGMP

NOS

cGMPcGMP

sGCsGCpGCpGC

NO

ANP

BNP CO

Relaxation

CNP

Endo

Smooth

muscle


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2

AIR

O2O2

Air

CONO

ANP

BNP

PGI2

K+v

Postnatal Circulation


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2

Summary

Fetal circulation uniquely adapted to the

intra-uterine life- Low PO2 and non-

respiring lungs

Preparation for post-natal adaptation

occurs throughout fetal life Understanding these adaptations essential

to management of infants in NICU


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2

Normal

Post natal

Circulation

Normal Transition

Systemic Blood Pressure

Pulmonary arterial pressure

Left

Atrium

Right

Atrium


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2

O2 Saturations in Fetal Circulation

Ductus Venosus Shunt

30-50% of umbilical venous blood shunted

thru DV

Percent shunted declines with gestation

Rest of umbilical venous blood-left and

right lobes of liver

Left hepatic vein (65% Sat)-across PFO

Portal venous blood (40% Sat) mostly to

right lobe of liver


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2

PDA - Compensatory Mechanism?

EC SMLumen

Low PO2

Lumen pressure

eNOS

Cox1,2

Hox 1,2

Oxygen

Pressure

ET-1

Cyp 450

NO cGMP

PGE2 cAMP

CO cGMP

Ca++

Kv

Kv

PDA Physiology


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3

Flow Across PDA

Regulated by PVR in the fetus

Response to blood gas changes- opposite

to pulmonary circulation

Response to vasoactive substances-

PGE2, NO, ATP, K+ channel blockers etc

similar to pulmonary vessels


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3

Breath NO LevelsBreath NO Levels -- InfantsInfants

0

20

40

60

80

100

120

140

Preterm Term

Nasal NO Ex NO-Vent

Partsperbillion

Williams et al Ear Hum Dev 03

Leipala et al Eur J Ped 04

Right Lobe Left Lobe

DV

Portal

Vein


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3

EC VSMLumen

Low PO2

Lumen pressure

eNOS

Cox1,2

Hox 1,2

ET-1

Cyp 450

cGMP

cAMP

cGMP

Ca++

Kv

Ca++

ETA

EET

Lip Oxy TxA2TxB2

Fetal Pulmonary Artery

EC VSMLumen

Estrogen

Steroids

Shear Stress

eNOS

Cox1,2

SOD-1,2

GC

AC

SMC growth

Kv

Ca++

Maturation of vasodilator system during gestation


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3

Basal ATP levels in fetus

0 800

PA PA Sat 59%

LA LA Sat 81%

0 5

PA

LA

Blood ATP

Plasma ATP

*

*

Advantages of sheep model

Gest age 140 days

Carry single or twins

Fetus large enough

for instrumentation

Uterus is quiescent


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Superoxide Dismutases

NOS

OO22GCGC--cGMPcGMP

KK++

NONONOSNOS

EndoEndo SMCSMC

COXCOX PGI2PGI2 ACAC--cAMPcAMPDistDist

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